Mechanism of neuronal versus endothelial cell uptake of Alzheimer's disease amyloid beta protein.
Mechanism of neuronal versus endothelial cell uptake of Alzheimer's disease amyloid beta protein.
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DOI：
10.1371/journal.pone.0004627
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Poduslo JF
中科院分区：
文献类型：
--
作者：
Kandimalla KK;Scott OG;Fulzele S;Davidson MW;Poduslo JF
阿尔茨海默病(AD)的特征是皮质和海马区明显的神经变性；过度磷酸化的tau蛋白在神经元内缠绕；以及脑实质和脑血管中β-淀粉样蛋白(Aβ)40和42的聚集。目前的认识认为，AD是由于A-β蛋白在血脑屏障的清除效率低下而导致神经元积聚而引发的，将神经血管单位置于AD病理生理学的中心。本研究的目的是探讨Aβ蛋白在神经血管单位的主要成分、神经元和血脑屏障内皮细胞中内化的细胞机制。用荧光素标记的Aβ40(F-Aβ40)处理野生型(WT)小鼠脑片的激光共聚焦显微照片显示，该蛋白通过非饱和、能量非依赖性和非内吞途径选择性地聚集在皮质和海马神经元的亚群中。这一突破性的发现挑战了传统的观点，即Aβ蛋白通过受体介导的内吞作用被神经元内化，并通过激光共聚焦显微镜和流式细胞仪研究在分化的PC12细胞和大鼠原代海马神经元中得到验证。显微镜研究表明，被分化的PC12细胞或β神经元内化的F-Aβ40或F-A RPH 42有很大比例位于内小体或溶酶体室外，可在不降解的情况下积聚。相反，BBME细胞对F-Aβ40的摄取依赖于能量，并在酸性细胞器中积累蛋白质，表明摄取内吞。Aβ40在神经元和血脑屏障内皮细胞中内化的这种显著差异可能为理解不同细胞如何差异调节Aβ蛋白提供重要线索，并有助于解释皮质和海马神经元对Aβ毒性的脆弱性。
Alzheimer's disease (AD) is characterized by significant neurodegeneration in the cortex and hippocampus; intraneuronal tangles of hyperphosphorylated tau protein; and accumulation of β-amyloid (Aβ) proteins 40 and 42 in the brain parenchyma as well as in the cerebral vasculature. The current understanding that AD is initiated by the neuronal accumulation of Aβ proteins due to their inefficient clearance at the blood-brain-barrier (BBB), places the neurovascular unit at the epicenter of AD pathophysiology. The objective of this study is to investigate cellular mechanisms mediating the internalization of Aβ proteins in the principle constituents of the neurovascular unit, neurons and BBB endothelial cells. Laser confocal micrographs of wild type (WT) mouse brain slices treated with fluorescein labeled Aβ40 (F-Aβ40) demonstrated selective accumulation of the protein in a subpopulation of cortical and hippocampal neurons via nonsaturable, energy independent, and nonendocytotic pathways. This groundbreaking finding, which challenges the conventional belief that Aβ proteins are internalized by neurons via receptor mediated endocytosis, was verified in differentiated PC12 cells and rat primary hippocampal (RPH) neurons through laser confocal microscopy and flow cytometry studies. Microscopy studies have demonstrated that a significant proportion of F-Aβ40 or F-Aβ42 internalized by differentiated PC12 cells or RPH neurons is located outside of the endosomal or lysosomal compartments, which may accumulate without degradation. In contrast, BBME cells exhibit energy dependent uptake of F-Aβ40, and accumulate the protein in acidic cell organelle, indicative of endocytotic uptake. Such a phenomenal difference in the internalization of Aβ40 between neurons and BBB endothelial cells may provide essential clues to understanding how various cells can differentially regulate Aβ proteins and help explain the vulnerability of cortical and hippocampal neurons to Aβ toxicity.
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